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Endothelial mechanisms of impaired lung gas exchange by HIV

Award Number: R56HL125043
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2014
PERIOD OF PERFORMANCE END DATE: 10/31/2016

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Endothelial mechanisms of impaired lung gas exchange by HIV - DESCRIPTION (provided by applicant): One of the most prevalent morbidities in HIV seropositive (HIV+) patients is chronic obstructive pulmonary disease (COPD), such as emphysema, present in ~20%. HIV is now recognized as a risk factor for COPD, independent of cigarette smoking (CS). However, the mechanisms of HIV associated chronic lung disease remain poorly understood. Chronic inflammation and the associated endothelial activation that mediate the development of end-organ disease in HIV+ patients are likely to be major contributors to COPD pathogenesis. One of the earliest detected pulmonary manifestations of HIV infection is a decrease in gas transfer across the alveolar-capillary membrane, reflected by a reduced diffusing capacity of the lung for carbon monoxide (DLCO) that is present even in individuals on antiretroviral therapy (ART). Radiographically, the predominant finding to account for low DLCO in HIV+ patients is emphysema, which appears more severe and diffuse, and with greater lower lobe involvement in HIV+ compared to HIV- patients. This distribution is similar to that found in alpha-one antitrypsin (A1AT) deficient patients, who also present with emphysema at relatively young ages and worsen with smoking. Since in addition to its antielastase activity, we and others have demonstrated that A1AT is protective to endothelial cells, relative A1AT deficiency combined with HIV induced endothelial activation may cause endothelial dysfunction, reduced DLCO, early emphysema and enhanced susceptibility to a decline in lung function. Thus, the pathogenesis of emphysema in HIV+ patients may be initiated primarily in the vascular compartment and may be distinct from that in HIV- patients. We will test the hypothesis that the impaired pulmonary gas exchange in HIV+ patients is explained by lung microvascular dysfunction synergistically aggravated by cigarette smoke and identified by biomarkers of endothelial activation and dysfunction. To test this hypothesis, we will use a complementary translational approach that takes advantage of the unique strengths of our multiple PI team. We will leverage an efficient study design using existing biospecimens and clinical data from demographically similar HIV+ and HIV- patients, complemented by studies of relevant human lung microvascular endothelial injury models that will synergize with proteomic analysis of airspaces. This proposal will test the novel paradigm that endothelial activation is an initiator o impaired gas exchange and of the development of chronic lung disease in HIV infection. Understanding the mechanisms of impaired gas exchange is essential as a low DLCO is a risk factor for death in HIV+ patients, and our results can identify targets for new individualized treatments, identify potential biomarkers for future validation studies, and inform the design of clinical trials to improve the health of HIV+ patients with chronic lung disease. Statement of Relevance HIV infection is associated with impairment in gas exchange in the lung; this defect is associated with an increased risk of death. The studies proposed will advance our understanding of the mechanisms for the development of gas exchange abnormalities in HIV, and will inform the development of tailored therapeutic interventions to improve the long-term function and survival of HIV infected individuals.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = -$567 )
2018	2014	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	2	8/8/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$567
														Subtotal = -$567

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2014	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Lung Diseases Research	001	1	9/29/2017	NEW	-$567
2017	2014	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	002	2	9/29/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$567
2017	2014	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	2	2/22/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	NATIONAL JEWISH HEALTH	1400 JACKSON STREET	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	2	2/17/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$26,366
2016	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Lung Diseases Research	001	1	2/20/2016	NEW	$26,366
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Lung Diseases Research	000	1	8/4/2015	NEW	-$137,042
2015	2014	NATIONAL JEWISH HEALTH	1400 JACKSON STREET	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	001	2	8/4/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$137,042
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $683,614 )
2014	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Lung Diseases Research	000	1	9/11/2014	NEW	$683,614
														Subtotal = $683,614

Grand Total All Awards = $683,047

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Endothelial mechanisms of impaired lung gas exchange by HIV

Award Number: R56HL125043

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/11/2014

PERIOD OF PERFORMANCE END DATE: 10/31/2016

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